An international collaboration of researchers has identified several progressive series of mutations that occur in tumor cells responsible for aggressive subsets of neuroblastoma that relapse after chemotherapy. Neuroblastoma, a solid tumor of nerve tissue, is the most common cancer in infants, and its cure rates lag behind those for other pediatric cancers.

The investigators, including co-study leader Derek Oldridge from the lab of John M. Maris, MD, at The Children’s Hospital of Philadelphia, performed extensive genetic sequencing of 23 pairs of tumors obtained at initial diagnosis and at relapse from the same patients. This allowed the researchers to compare the tumors’ genetic and molecular characteristics. Among the 23 relapsed tumors, 18 harbored mutations that boosted signals funneling into a biological pathway called RAS-MAPK, which made neuroblastoma progress.

Clonal selection is a process by which mutations allow malignant cells’ descendants to become more dominant. For example, a mutation that enables a cell to grow and divide rapidly could give it a head start at relapse compared to other cells within the tumor population.

The researchers published their results in Nature Genetics, demonstrating that relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Their findings offer new prospects to design personalized treatments for children with neuroblastoma. A group of drugs called MEK inhibitors that target those cancer-driving mutations are already available. Previous research in cell cultures and animal studies has shown that MEK inhibitors slowed tumor growth and improved the animals’ survival.

“Our preclinical findings strongly suggest that MEK inhibitors may directly benefit patients who suffer a relapse and have mutations in the RAS-MAPK pathway,” said Dr. Maris, a pediatric oncologist at Children’s Hospital who holds the Giulio D’Angio Chair in Neuroblastoma Research. “We think one of the most important conclusions from this work is that we should completely change our approach to relapsed disease. Until now, tumor biopsy was not necessary at relapse as it was very unlikely to change clinical practice. Now that we know that sequencing these resistant cancers can nominate novel therapies, we think we are entering a new era of personalized therapeutic decision making for children with currently incurable disease.”

It is likely that other biological pathways also contribute to the high risk of treatment failure in certain neuroblastoma cases. Dr. Maris recently received a new grant from the National Cancer Institute to investigate the role of the LMO1 gene locus in the initiation, growth, and survival of neuroblastoma, building on his lab’s discovery of LMO1 as a major oncogene in this disease. Greater understanding of key cellular networks such as RAS-MAPK and LMO1 will help researchers to develop rational, evidence-based strategies for precision medicine in neuroblastoma and other cancers.

In the U.S., about 800 new cases of neuroblastoma are diagnosed each year. It accounts for 7 percent of all childhood cancers, but it causes 15 percent of all childhood cancer deaths.

The study that appeared in Nature Genetics also involved Thomas F. Eleveld, MSci, and Jan J. Molenaar, PhD, of the Academic Medical Center of the University of Amsterdam; and Virginie Bernard, PhD, and Gudrun Schleiermacher, MD, PhD, of the Institut Curie in Paris. Funds from the National Cancer Institute, the Children’s Oncology Group, and the University of Pennsylvania Genome Frontiers Institute supported this study.

“It has been estimated repeatedly over the past 40 years that 75 to 80 percent of pharmaceuticals possess insufficient labeling information for dosing, safety, or efficacy in children,” the authors note in the Pediatrics article. “To address these knowledge gaps, large EHR databases” — such as those offered by CER2 — “from diverse practice settings are particularly helpful resources because they can link prescribing data with clinical outcomes, can identify cohorts of children for more detailed study, and can drive decision support to improve care based on medical evidence.”

In addition to Dr. Fiks, Children’s Hospital’s Robert Grundmeier, MD, of the Department of Biomedical and Health Informatics; Jennifer Steffes of the American Academy of Pediatrics; David Kaelber, MD, of Case Western Reserve University, Cleveland; Wilson Pace, MD, of the American Academy of Family Physicians National Research Network; William G. Adams, MD, of Boston University; and Richard Wasserman, MD, of the University of Vermont, contributed to the article.

Much of Dr. Fiks’ work has been focused on using EHRs and technology to improve patient care. For example, in April, Dr. Fiks published a separate Pediatrics study that showed an electronic portal focused on asthma — which the researchers call MyAsthma and is linked to patients’ EHRs — helped improve asthma care and outcomes. MyAsthma features tools to track symptoms, a timeline of asthma control assessments, asthma educational information, and details on each patient’s care plan.

CER2 was initially established to conduct research into pediatric medications’ effectiveness and side effects. Building upon this focus, CER2 investigators are examining the treatment of hypertension, which the authors note affects between 2 and 4 percent of children, but “often remains undiagnosed.” Ultimately, the consortium seeks to improve the recognition and treatment of pediatric hypertension by using EHR tools to automatically alert physicians.

“The goal of CER2 is to engage scholars from around the country in a diverse range of research projects focused on pediatric medication, safety, and effectiveness, as well as other areas including preventative care, treatment of acute conditions, and chronic disease management,” the authors wrote.

The “Home Plate” study will include parents and mentors who will participate in weekly cooking classes for six weeks. The trained study staff will collect 24-hour dietary recalls from adult caregivers, and the results will then be used to calculate the energy density of the children’s diets.

A unique aspect of the study is that investigators are working closely with several respected West Philadelphia community organizations including WIC,Early Head Start, and The Enterprise Center, who have been instrumental in recruiting and engaging interested families in the study.

“Twenty parents and five mentors will participate in each six-week series of classes, where they will come together weekly to cook and eat a meal, with the goal of learning by doing, rather than through didactic instruction alone,” Dr. Virudachalam said. “We hope that parents who participate in the classes will gain both the confidence and skills to regularly prepare healthy food at home, resulting in improved diets for the entire family.”

In previous research, Dr. Virudachalam examined data from the National Health and Nutrition Examination Survey 2007-2008 to determine the prevalence and patterns of cooking dinner at home in the U.S. The analysis defined the scope of just how large of an issue home dinner preparation habits are for the daily lives of Americans.

“We found that while half of all Americans reported that they always cook dinner at home, the remainder obtain many or most dinners away from home,” Dr. Virudachalam noted. “Preparing healthy food at home is potentially one of the most significant points for effective interventions to curb the obesity epidemic, both at the individual and population level.”

Dr. Virudachalam and her co-authors concluded that dinner preparation habits vary with socio-economic status and race/ethnicity. Poorer, less educated households were more likely to either always or never cook dinner at home, and wealthier, more educated households were more likely to sometimes cook dinner at home.

“Half of all African American and Latino children born in the year 2000 will develop diabetes or heart disease [due to obesity],” Dr. Virudachalam stated in her analysis.

She suggested that tailored interventions could help families limit fast food and promote healthy eating from home, which are the strategies that the Home Plate study is serving up. It has the potential to help parents learn how to make nutritious food choices that will become part of an overall healthier lifestyle for their families.

“If successful, the Home Plate intervention would provide a low-cost model for changing eating behaviors that could be replicated by community-based organizations throughout the country,” said Dr. Virudachalam, who also is an assistant professor of Pediatrics at CHOP and the Perelman School of Medicine at the University of Pennsylvania. “Such interventions are crucial for successfully addressing the obesity epidemic.”

A $750,000 investment from The Aramark Charitable Fund to the Healthy Weight Program at CHOP is funding the Home Plate study, which is expected to be completed in October 2017.

Dr. Adamson is the only pediatric oncologist to currently serve on the NCAB, and he will work to ensure the voices of the pediatric cancer community are heard by decision makers in the federal government.

“We are extremely proud of Dr. Adamson on his appointment by President Obama to this distinguished advisory board,” said Joseph St. Geme, MD, physician-in-chief and chair of the Department of Pediatrics. “This recognition is a testament to his dedication and leadership within the medical community in furthering research to advance treatment for childhood cancer.”

This appointment follows the President’s announcement in the State of the Union address of a Precision Medicine Initiative that will harness research and technology toward developing individualized treatments for many diseases.

An internationally recognized leader in pediatric cancer drug development, Dr. Adamson has served as Chair of The Children’s Oncology Group (COG), the world’s largest organization devoted exclusively to childhood and adolescent cancer research, since 2010. Through COG, he coordinates leading pediatric cancer researchers at CHOP and across the country who are hard at work on the most promising new therapies.

From 1999 to 2014, Dr. Adamson was Chief of the Division of Clinical Pharmacology and Therapeutics at CHOP, and he also served as Director of the Office of Clinical and Translational Research from 2005 to 2011. Prior to joining CHOP in 1999, he was a member of the Pediatric Oncology Branch of the NCI.

To read more about cancer care and research at The Children’s Hospital of Philadelphia, see the Cancer Center.

Pediatric traumatic brain injury (TBI) will become a major cause of death and disability of children within the next several years, The World Health Organization predicts, as many third-world countries become urbanized. Whether the injuries result from motor vehicle crashes on the road or sports collisions on the field, researchers have shown that all cases of TBI can be serious concerns.

A TBI is caused by a bump, blow, or jolt to the head or a penetrating head injury. The majority of TBIs that occur each year are concussions or other forms of mild TBI. Some concussion symptoms may appear immediately after the injury, while others may not show up for several days. They can include headache, nausea, dizziness, sleep problems, difficulty concentrating, and moodiness.

Todd Kilbaugh, MD, an anesthesiologist and intensivist with the Department of Anesthesiology and Critical Care Medicine at The Children’s Hospital of Philadelphia; colleagues from Lund University, Sweden; and senior collaborator Susan Margulies, PhD, from the Department of Bioengineering at the University of Pennsylvania, have developed comprehensive large animal models of pediatric TBI. The study team reported in two recent publications that ongoing injury persisted at a submolecular level 24 hours after a mild to moderate brain injury occurred.

The investigators hypothesize that alterations in mitochondrial function could interfere with the brain’s ability to limit damage, which is called neurodegeneration, and heal itself, which is called neuroregeneration, leading to long-term inflammation and problems with the way the brain affects emotion, behavior, and learning. Mitochondria are organelles that are essential to the production of the body’s energy supply and also regulate a cells’ everyday housekeeping.

“Even in critical illness, not just traumatic brain injury, we believe that these little organelles can act like a light switch that controls whether a cell lives or dies,” Dr. Kilbaugh said.

The researchers used sophisticated technology called high-resolution respirometry to analyze minute tissue samples. They measured the amount of oxygen the tissue was using to pinpoint the real-time activity of mitochondrial machinery called the electron transport system.

“For the first time, this gave us a window into how the brain responds to the energetic crisis that it goes under in response to an injury,” Dr. Kilbaugh said. “We took apart each individual aspect of the electron transport system to figure out where things are working and where things are not working.”

By better understanding the bioenergetics failure that occurs within the mitochondria, the researchers aim to develop new pharmacologic approaches or interventions that can support the health and energy output of cells during a crisis. Finding novel ways to quickly help children who experience TBI could prevent a lifetime of medical care and related costs to society.

“Like an athlete who needs to exercise, run, and get stronger after an injury, there are likely parts of the brain and mitochondria that we can improve after injuries to produce more energy in the brain to help with recovery and healing processes,” said Dr. Kilbaugh, who also is an assistant professor of Anesthesiology and Critical Care at the Hospital of the University of Pennsylvania.

Results of the studies appeared in the journals Experimental Neurology and PLoS One. Dr. Margulies, who leads the Injury Biomechanics Lab at the University of Pennsylvania, is the senior author.

Bench-to-bedside research at The Children’s Hospital of Philadelphia involves talented scientists who make discoveries in the lab that translate into investigations of clinical applications. CHOP experts studying T-cell acute lymphoblastic leukemia (T-ALL) are taking this model one step further — bench to bedside and back again — by turning around their findings from clinical studies to better inform new series of basic science experiments.

T-ALL is a cancer of a type of white blood cells called T-lymphocytes. Normally, T-lymphocytes help fight infections. When the bone marrow and thymus gland produce too many immature T-lymphocytes, the body’s ability to fight infections becomes compromised.

Despite advances in T-ALL treatment, between 15 and 20 percent of children and young adults who achieve an initial complete remission will have the disease return (relapse). They may need more intensive therapy or alternative approaches, but physicians do not yet have a reliable way of predicting which patients are at high risk of relapse.

David Teachey, MD, an attending physician and researcher at CHOP with expertise in both oncology and hematology, is leading a study involving researchers from across the country who aim to develop new insights to improve risk stratification of T-ALL by increasing their understanding of its biochemical underpinnings. This work is being funded by the National Cancer Institute through an R01.

“This new grant is trying to tackle two problems,” Dr. Teachey said. “One is we don’t know how to identify the kids who relapse when they walk in the door — you don’t know until it’s too late. And two, we need to develop new therapies for the ones who do relapse.”

The study team will analyze patient samples collected from an international, phase 3 clinical trial called AALL1231 that Dr. Teachey chairs for the Children’s Oncology Group. AALL1231 includes approximately 1,200 children and young adults from more than 200 hospitals, and the goal is to determine if standard chemotherapy with or without the drug bortezomib is more effective in treating T-ALL.

In the new study, the investigators will take a protein level approach to help identify subsets of patients with T-ALL who are likely to relapse. They will study participants’ leukemia cells and the proteins that they make, looking for patterns that clinicians could use as a high-risk molecular signature. Next, they will see if there is any correlation between these protein profiles and results from sophisticated next-generation sequencing that allows researchers to detect minute levels of cancer cells that remain after intensive, high-dose, multi-agent chemotherapy.

If the study team can figure out which proteins are abnormal in the patients who do poorly, then they could eventually test drugs that target those altered pathways. They will accomplish this by generating mouse models using the participants’ leukemia cell samples. Since the patients already are involved in the AALL1231 trial, the study team will know who did well and who went on to relapse, so they will be able to see how different therapies affect their prognosis.

For instance, the JAK/STAT signaling pathway is implicated in a high-risk subtype of T-ALL, according to a paper published in the journal Blood earlier this year by Dr. Teachey and colleagues. If drugs are available that can turn off that pathway, then they may be beneficial in combination with existing chemotherapy agents. The study team intends to identify other signaling pathways that are abnormally activated in T-ALL, which may give them clues to better predict chemotherapy response and resistance.

“In the big picture, the hope is the correlative biology performed in the lab will let us learn how to better diagnosis and treat children with T-ALL. Then, we can open a future trial using new drugs to treat children who we think aren’t going to do well and improve their chance of being cured,” Dr. Teachey said.

The project will involve researchers from Seattle Children’s Hospital; UCSF Medical Center, California; The University of Texas MD Anderson Cancer Center; and the University of Texas Southwestern Medical School, in addition to researchers from The Children’s Hospital of Philadelphia.

The way viruses can infect the nervous system is at the heart of neurovirology, an important field of study that includes not only neuroscience and virology, but also molecular biology and immunology.

Steven D. Douglas, MD, chief of the Section of Immunology at The Children’s Hospital of Philadelphia, has spent the last 40 years investigating the biology of immune cells, with particular relevance to potential treatment for human immunodeficiency virus (HIV) infection. His research has encompassed basic studies of cell biology, identification of mechanisms of HIV infection, and conducting clinical trials in HIV-infected patients.

As a result of his seminal work, Dr. Douglas received the Lectureship Award from the International Society for NeuroVirology (ISNV). The Lectureship Award recognizes a leading investigator for a systematic body of scientific research in neurovirology.

Dr. Douglas delivered the Paradigm Builder Lecture to the ISNV in June at the organization’s 13th annual symposium. The lectureship specifically highlights “the establishment of well-defined scientific frameworks within which theories, laws, generalizations, and supporting experiments are formulated and planned.”

“Dr. Douglas has been in the forefront of research in immunology,” according to a statement on the ISNV website. For the past 35 years, he has been at The Children’s Hospital of Philadelphia and at the University of Pennsylvania, where he is a professor of Pediatrics in the Perelman School of Medicine.

Starting in the late 1970s, Dr. Douglas established laboratory methods for investigating two types of immune cells: monoctyes and macrophages. Those cell culture methods have enabled laboratory research throughout the world. Dr. Douglas was among the first scientists to discover that HIV-1 infects macrophages derived from monocytes. He first showed that an important chemical, substance P, exists on these cells, and that it plays a crucial role in neurological manifestations of AIDS. He then identified a pathway shared by substance P and a particular cell receptor as a potential target for treating HIV infection.

Dr. Douglas has received continuous research funding for the past four decades from various centers within the National Institutes of Health. Currently, he is collaborating with co-investigators from Temple University in a joint $4.3 million NeuroAIDS grant from the National Institute of Mental Health. This grant funds research on new methods to eradicate HIV that lurks in brain cells despite conventional antiviral treatments.

The Paradigm Lectureship Award citation notes that “Dr. Douglas’ research has intersected the disciplines of psychiatry, immunology, neurology, and AIDS.” Although Dr. Douglas’ previous honors, research publications, and memberships on scientific committees are too numerous to mention, he currently serves as a member of the Scientific Oversight Leadership Committee for the International Maternal Pediatric Adolescent AIDS Clinical Trials.

Dr. Douglas is the seventh scientist to receive the Paradigm Lectureship Award, established in 2006.

Researchers’ understanding of the molecular pathways involved in cancer has enabled the development of targeted drugs for diseases such as pediatric and adult recurrent medulloblastoma, a type of rare brain cancer.

“It is terrific to see this exciting application of precision medicine to brain tumors that arise in children and adults,” Dr. Curran said. “While there is a long way still to go, and drug resistance is an issue, this is an extremely promising result.”

Dr. Curran, who has a background in brain development and cancer research, has a longstanding interest in finding drugs to treat medulloblastoma with fewer long-term side effects than current surgery, chemotherapy, and radiation approaches. New therapies especially are crucial for patients with high-risk or recurrent/relapsed disease who have poor chances of survival.

Medulloblastoma is comprised of four molecular subgroups. The studies focused on the SHH-MB subgroup, which is associated with activation of the sonic hedgehog (SHH) pathway. The SHH signaling pathway is crucial for the normal development of the cerebellum, a part of the brain that helps to coordinate movements such as posture, balance, and speech. Researchers suspect that overactive SHH signaling can cause tumors to proliferate.

Previous research suggests that SHH pathway inhibitors, such as vismodegib, could be useful to treat patients in the SHH-MB subgroup. Dr. Curran identified the SHH pathway as an ideal target for medullobastoma therapies after noting that Gorlin syndrome, a disorder caused by a mutation in the gene associated with the SHH pathway, is associated with a predisposition to these brain tumors.

In the current studies, participants’ tumors were prescreened for SHH-pathway activation. Out of 20 participants with recurrent SHH-MB who received oral vismodegib daily, the researchers observed a reduction in tumor area in three adults and a child. While this disease response was seen in only a few patients, prolonged disease stabilization occurred in 41 percent of patient cases with SHH-MB, which indicates that vismodegib has favorable activity. They observed no responses in patients with recurrent non-SHH-MB.

“This work represents the culmination of efforts of a large collaborative team starting in 1995 to develop a molecular-targeted treatment for medulloblastoma,” Dr. Curran said. “The clinical results are very consistent with preclinical studies indicating that the HH pathway inhibitor, vismodegib, is efficacious in a particular molecular subtype of tumor.”

The variable response to vismodegib in patients with recurrent SHH-MB suggests the presence of additional tumor mutations that may occur downstream of the transmembrane protein called Smoothened that the drug helps to block. The investigators concluded that while SHH inhibitors “should be advanced in SHH-MB studies, molecular and genomic work remains imperative to identify target populations that will truly benefit.”

The SHH-MB subgroup appears to be less common in the pediatric population than in the adult population, so the researchers do not have enough data yet to make any conclusions about using vismodegib for children. In future research studies, they emphasized that children exposed to vismodegib should continue to be monitored for safety and efficacy.

The studies were performed as part of the Pediatric Brain Tumor Consortium, a multidisciplinary cooperative research organization devoted to the study of correlative tumor biology and new therapies for primary central nervous system tumors of childhood. The co-investigators hold positions at St. Jude Children’s Research Hospital, Memphis; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, N.C.; Center for Neuroscience Research, Children’s National Medical Center, Washington, D.C.; Ann & Robert Lurie Children’s Hospital of Chicago; Helen Diller Cancer Center, University of California, San Francisco; Texas Children’s Cancer Center, Houston; National Cancer Institute, Bethesda, MD; and Cincinnati Children’s Hospital.

While young adults are essential to the implementation of the Affordable Care Act (ACA), the process of applying for health insurance using the federal insurance marketplace HealthCare.gov can be confusing to them, according to a small, observational study.

Historically, a significant part of the young adult population in the U.S. has been uninsured. Under the ACA’s goal to expand access to health insurance for everyone, they have new choices when shopping for affordable insurance plans. They can compare insurance options on HealthCare.gov with plans outside the marketplace such as those offered by employers, schools, or their parents’ health insurance.

“Most of the young people in our study were buying health insurance for the first time, since many had previously been on their parents’ plans, and they found the process of selecting from 30 plan options in Philadelphia challenging and overwhelming,” said Charlene Wong, MD, principal investigator of the study published in the Journal of Adolescent Health. “The young adults’ thoughts on health insurance and HealthCare.gov, for example what they are looking for and the challenges they identified, can inform more effective outreach efforts and improvements to the website.”

In the study conducted from January to March 2014, Dr. Wong and colleagues described young adults’ experiences using HealthCare.gov and their attitudes toward health insurance, health insurance literacy, and benefit and plan preferences. Thirty-three study participants’ ages 19 to 30 who lived in Philadelphia County and were highly educated spent up to 30 minutes exploring HealthCare.gov. During the sessions, the study team recorded study participants’ “think aloud” reactions in real-time.

For example, one participant said, “I just wasn’t able to comprehend all of the things on HealthCare.gov — I got confused. I’m not a person to give up, not at all — but with the system, I just wanted to quit.”

Study participants struggled with many of the basic insurance terms that appeared on the website. Of the 33 participants, 48 percent incorrectly defined “deductible” and 78 percent incorrectly defined “coinsurance.”

The investigators conducted follow-up interviews with the participants to discuss their perspectives in more detail and also to identify factors important to their enrollment decisions. The results showed that deductible and premium amounts and preventive care coverage were most important to the participants’ plan selection.

“Based on this study, we developed recommendations for improvements to HealthCare.gov that have been disseminated to the Office of Health Reform,” said Dr. Wong, who is a fellow with the Craig-Dalsimer Division of Adolescent Medicine program at The Children's Hospital of Philadelphia. “For example, the young adults suggested that pop-up explanations that appear when your cursor is over an important term like ‘deductible’ would have been helpful. We also have ongoing work on the tools available to consumers on HealthCare.gov and other state-based insurance marketplaces to help simplify or support them in making informed health insurance choices.”

The next open enrollment period for HealthCare.gov and other state-run health insurance marketplaces is November 2015.